A number of derivatives of acridine have recently been studied for antitumour activity. Earlier work with simple 9-anilinoacridines showed that 4'-(9-acridinylamino) methanesulphonanilide or AMSA had good antitumour activity on the mouse L1210 leukemia model (G. J. Atwell, B. F. Cain and R. N. Seelye, J. Med. Chem., 15, 611-615 (1972). A study of the effects of various substituents placed on the anilino ring on biological activity revealed that a methoxy group at the 3'-position, meta to the methanesulfonamide, increased dose potency, and led to the clinical agent 4'-(9-acridinylamino)methanesulphon-m-anisidide, m-AMSA or amsacrine. (B. F. Cain and G. J. Atwell, Europ. J. Cancer, 10, 539-549 (1974) and see also the following articles: B. F. Cain, G. J. Atwell and W. A. Denny, J. Med. Chem., 18, 1110-1117 (1975); B. F. Cain, W. R. Wilson and B. C. Baguley, Molecular Pharmacology, 12, 1027-1035 (1976); B. F. Cain, G. J. Atwell and W. A. Denny, J. Med. Chem., 19, 772-777 (1976); B. F. Cain and G. J. Atwell, J. Med. Chem., 19, 1409-1416 (1976); M. J. Waring, Europ.J.Cancer, 12, 995-1001 (1976); B. C. Baguley, W. R. Wilson, L. R. Ferguson and B. F. Cain, Current Chemotherapy, pp. 1210-1212 (1978); W. A. Denny, G. J. Atwell and B. F. Cain, J.Med.Chem., 21, 5-10 (1978).)
The antitumour activity of a large range of AMSA and m-AMSA analogues containing variously substituted acridine and anilide nuclei has now been investigated, see for example G. J. Atwell, B. F. Cain and R. N. Seelye, J.Med.Chem., 15, 611-615 (1972); B. F. Cain, R. N. Seelye and G. J. Atwell, J.Med.Chem., 17, 922-930 (1974); B. F. Cain, G. J. Atwell and W. A. Denny, J.Med.Chem., 18, 1110-1117 (1975), and J.Med.Chem., 19, 772-777 (1976); B. F. Cain and G. J. Atwell, J.Med.Chem., 19, 1124-1129 and 1409-1416 (1976); G. J. Atwell, B. F. Cain and W. A. Denny, J.Med.Chem., 20, 520-526, 987-996, 1128-1134, and 1242-1246 (1977); W. A. Denny, G. J. Atwell and B. F. Cain, J.Med.Chem., 21, 5-10 (1978); W. A. Denny and B. F. Cain, J.Med.Chem., 21, 430-437 (1978); B. F. Cain, B. C. Baguley and W. A. Denny, J.Med.Chem., 21, 658-668 (1978); L. R. Ferguson and W. A. Denny, J.Med.Chem., 22, 251-255 (1979); W. A. Denny, G. J. Atwell and B. F. Cain, J.Med.Chem., 22, 1453-1460 (1979); L. R. Ferguson and W. A. Denny, J.Med.Chem., 23, 269-274 (1980); B. C. Baguley, W. A. Denny, G. J. Atwell and B. F. Cain, J.Med.Chem., 24, 170-177 and 520-525 (1981); L. R. Ferguson and B. C. Baguley, Mutation Research, 82, 31-39 (1981); W. A. Denny, B. F. Cain, G. J. Atwell, C. Hansch, A. Panthananickal and A. Leo J.Med.Chem., 25, 276-315 (1982); G. W. Rewcastle, B. C. Baguley and B. F. Cain, J.Med.Chem., 25, 1231-1235 (1982); B. F. Cain, G. J. Atwell, B. C. Baguley and W. A. Denny, U.S. Pat. No. 4,472,582, issued Sept. 18, 1984; and B. F. Cain and G. J. Atwell, U.S. Pat. No. 4,366,318, issued Dec. 28, 1982.
During this work it was found that a number of groups other than methoxy placed at the 3'-position (e.g., F, Cl, NO.sub.2, Br) abolished activity and provided nontoxic compounds. Even groups of a similar steric and electronic nature to methoxy (e.g., --CH.sub.3, --OCH.sub.2 CH.sub.3, --OH and especially --NH.sub.2) provided compounds of decreased activity and (except for the --OH group) decreased potency. The strongly electronegative amino group (NH.sub.2) did not increase potency or activity over that of the unsubstituted AMSA (B. F. Cain, G. J. Atwell and W. A. Denny, J.Med.Chem., 18, 1110-1117, 1975).